Quaternary ammonium salts of 17alpha-aminoalkynyl-19-norsteroidal 3,5-dienes

ABSTRACT

NOVEL BIOCIDAL STERIODAL QUATERNARY AMMONIUM SALTS HAVE BEEN PREPARED WHICH ARE USEFUL AS AMEBICIDES, TRICOMONACIDES, FUNGICIDES, BACTERICIDES AND NEMATOCIDES.

United States Patent 3,721,688 QUATERNARY AMMONIUM SALTS OF 170:-

AMINOALKYNYL 19 NORSTEROIDAL 3,5-DIENES Gerhard R. Wendt, Haverton, Kurt W. Ledig, Philadelphia, and Donald W. Oliver, Phoenixville, Pa., assignors to American Home Products Corporation, New York,

No Drawing. Continuation-impart of application Ser. No. 796,909, Feb. 5, 1969. This application Mar. 30, 1970, Ser. No. 24,039 The portion of the term of the patent subsequent to Apr. 20, 1988, has been disclaimed Int. Cl. C07c 169/20 US. Cl. 260-3975 6 Claims ABSTRACT OF THE DISCLOSURE Novel biocidal steroidal quaternary ammonium salts have been prepared which are useful as amebicides, tricomonacides, fungicides, bactericides and nematocides.

CROSSFREFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of US. Pat. 3,575,967, filed Feb. 5, 1969 and granted April 20, 1971.

The quaternary ammonium salts of this invention are produced from compounds disclosed in US. 3,575,967, which patent is hereby incorporated by reference.

DESCRIPTION OF THE INVENTION This invention contemplates compounds of Formula I.

wherein R is alkyl of from -'1 to carbon atoms; R, is hydrogen or alkanoyl of from 2 to 5 carbon atoms and Y is wherein R is selected from the group consisting of phen(lower)alkyl and alkyl of from 1 to about 18 carbon atoms; R, and R are independently alkyl of from 1 to about 5 carbon atoms; X is halogen.

Special mention is made of a number of particularly valuable embodiments of this invention:

dl-diethyl [3-( 13-ethyl-17-hydroxygona 3,5-dien-17a-yl) 2-propynyl]methyl ammonium iodide;

dl-[3-(13-ethyl-17-hydroxygona-3,5-dien-17a-yl)-2- propynyl]trimethyl ammonium iodide;

dl- 3-( 13-ethyl-17-hydroxygona-3,5-dienl 7a-yl) -2- propynyl]dimethyl pentyl ammonium bromide;

dl-diethyl 3-( 13-ethyl-17-hydroxygona-3,5-dien-17u-yl)- Z-propynyllpentyl ammonium iodide; and

dl-benzyl 3- 13-ethyl-17-hydroxygona- 3,5-dien-17u-yl)- 2-propynyl] dimethyl ammonium iodide.

When used herein the term alkanoyl of from 2 to 5 carbon atoms, contemplates lower alkanoyl radicals such as acetyl, propionyl, butyroyl and pentanoyl. The terms halo and halogen are used to include chloro, bromo, fiuoro and iodo.

3,721,688 Patented Mar. 20, 1973 r'l'he compounds of the invention are prepared as follows:

wherein R, R R R R and X are the same as hereinabove described.

The reactants are combined in an organic solvent such as ether, acetonitrile, methanol, dimethylformamide, etc. The reaction may be conducted at room temperature or under reflux conditions.

The compounds of the invention are biologically active as bactericides, fungicides, amebicides, trichomonacides and nematocides.

Of special interest is the high in vivo amebicidal activity of the novel compounds of the invention.

The following in vivo procedure has been employed in evaluating the invention.

A laparotomy is performed on anesthetized, pathogenfree albino rats, their caecums exposed and approximatel 15,000 trophozoites of Endamoeba histolytica are injected into the lumen of the caecum. After 24 hours, healthy survivors are randomized into treatment groups and dosing is initiated. Dosing is oral, once daily for four days. On the fiftieth day the animals are sacrified their caecums removed and washed clean with saline. Caecal walls are scraped and the scraping mounted on a microscope slide and examined at 200x magnification. Eight rats are employed in this test.

No amoeba were observed in test subjects that were treated per os for four days with a daily dose of 400 mg./kg. of body weight.

The following examples are added to illustrate but not to limit the scope of the invention:

EXAMPLE I dl-Diethyl [3-( 13-ethyl-17-hydroxygona-3,5-dien-d7a-61 2-propynyl]methyl ammonium iodide To a solution of 910 mg. of dl-l7-(3-diethylamino-1- propynyl)-13-ethylgona 3,5 dien- 175-01, in ether was added 1 m1. of methyl iodide. The reaction mixture was kept at room temperature for 20 hours and the resulting precipitate filtered to give '600 mg. of the title compound; M.P. 140-150 C.

Found (percent): C, 61.36; H, 7.86; N, 2.38. C H, NOI requires (percent): C, 61.93; H, 8.08; N, 2.67. UV ethanol) )1 max. 222 m (e 27,000)

EXAMPLE H dl-[3-(l3-ethyl-17-hydroxygona-3,5-dien-17a-yl)-2- propynylJ-trimethyl ammonium iodide To a solution of 900 mg. of dL-I7-(3-dimethylaminol-propynyl) 13 ethylgona-3,5-dien-17B-ol in ether was added 1 ml. of methyl iodide. After keeping the reaction mixture for 20 hours at room temperature the resulting precipitate was filtered to give 500 mg. of the title compound, M.P. 254 C.

Found (percent): C, 60.33; H, 7.45; I, 25.18; C H NOI requires (percent): C, 60.59; H, 7.73; I, 25.61.

EXAMPLE III dl- 3-( 13-ethyl-l7-hydroXygona-3,5-dien-17a-yl)-2- propynyl]-dimethyl pentyl ammonium bromide A suspension of 900 mg. of dl-l7-(3-dimethylamino-1- propynyl)-13-ethylgona-3,5-dien-17 8-01, 50 ml. of acetonitrile and 1 ml. of bromopentane was refluxed for hours. The material was filtered off to give after recrystallization from methanol 700 mg. of the title compound; M.P. 278 C. dec.

Found (percent): C, 69.24; H, 9.15; N, 2.92; Br, 15.69. C H NOB1' requires (percent): C, 69.02; H, 9.18, N, 2.78; Br, 15.83.

EXAMPLE IV dl-benzyl 3-( 13-ethyl-17-hydroxygona-3,5-dien-17a-yl)- 2-propynyl1pentyl ammonium iodide A solution dl-17-(3-diethylamino-l-propynyl)-13-ethylgona-3,5-dien-17/3-ol in 30 ml. of acetonitrile, which had been prepared from its hydrochloride salt, was treated with 1 ml. of iodopentane and the reaction mixture refluxed for 4 hours. On cooling there was obtained a 1.4 g. yield of the title compound; M.P.'216-217 C.

Found (percent): C, 64.12; H, 8.38; N, 2.22; I, 22.39. C H NIO requires (percent): C, 64.23; H, 8.69; N, 2.42; I, 21.89.

EXAMPLE V al-diethyl[3-(13-ethyl-l7-hydroxygona-3,5-dien-17a-yl)- 2-propynyl]-dimethyl ammonium chloride EXAMPLE VI The procedure of Example III is repeated substituting stoichiometrical amounts of appropriately alkyl halides and phen(lower)alkyl halides:

wherein R, R R R R and X are as follows:

1. A compound selected from the group consisting of:

wherein R is alkyl of from 1 to 5 carbon atoms; R is hydrogen or alkanoyl of from 2 to 5 carbon atoms and Y is wherein R is selected from the group consisting of phen- (lower)-al-kyl and alkyl of from 1 to about 18 carbon atoms; R and R are independently alkyl of from 1 to about 5 carbon atoms; X is halogen.

2. A compound as defined in claim 1 which is: dl-diethyl[3 (13 ethyl 17 oxygona 3,5-dien-17u-yD-2- propynyl] -methyl ammonium iodide.

3. A compound as defined in claim 1 which is: dl-[3- (13 ethyl-17-hydnoxygona-3,5-dien-17a-y1)-2-propynyl]- trimethyl ammonium iodide.

4. A compound as defined in claim 1 which is: a l-[3- (13 ethy1-17-hydroxygona-3,5-dien-17a-yl)-2-propynyl]- dimethyl pentyl ammonium bromide.

5. A compound as defined in claim 1 which is: dl-diethyl[3 (13 ethyl 17 hydroxygona-3,5-dien-17a-yl)- 2-propynyl]pentyl ammonium iodide.

6. A compound as defined in claim 1 which is: d!- benzyl[3 (13 ethyl 17-hydroxygona-3,5-dien-17u-yl)- 2-propynyl]dimethyl ammonium chloride.

References Cited UNITED STATES PATENTS 3,575,967 4/1971 Ledig et al 260-397.5 3,536,703 10/1970 Coltan et al. 260-2395 3,553,211 1/1971 Ellis et a1. 260239.5

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 

